Relation between lactic acid and fatigue / PEM

[Dechi]

@Hip thanks again for your input. We're getting closer but there is still so much we don't understand !

 

[Wishful]

I'm unconvinced about the involvement of lactic acid, at least for my case. I can do hours of walking normally without PEM, but a short walk that required a different stride, such as lifting my feet due to crusty snow, does cause it. I think the symptoms are triggered by muscle tearing, which activates the t-cells, which activates the microglial cells, which cuases excess/unbalanced kynurenines. For me the delay is around 24 hrs, which would be expected for IFN-g release, and seems also proportional to tryptophan transport into the brain.

My upper body is in worse condition than my legs, and it only takes a couple of minutes of unusual activity (sawing wood, washing windows, or doing pretty much anything with my arms above my head, to cause PEM (24 hrs later). It doesn't sound like that's the sort of activity and time frame for lactic acid problems. It does fit t-cell activation.

I should also point out that my muscles don't feel more tired when the other symptoms are severe. My legs might feel up to a multi-hour bike ride, but my head wants a big pillow on the handlebars to collapse on. On those days, I simply lack the mental energy to be active.

Any simple way to test whether it's lactic acid build-up or IFN-g?

 

[Bansaw]

I'm unconvinced about the involvement of lactic acid,

For me, I am pretty convinced in my case.
For PEM my doc put me on an ammonia scavanging protocol to deal with my muscle aches etc after exertion. I tried to no avail. But then I started to try Bicarbonate of soda just after exercise and found this helped me a lot, almost eliminating muscle ache. So, for me personally, I think it was lactic, not ammonia.

 

[Hip]

I'm unconvinced about the involvement of lactic acid, at least for my case. I can do hours of walking normally without PEM, but a short walk that required a different stride, such as lifting my feet due to crusty snow, does cause it. I think the symptoms are triggered by muscle tearing, which activates the t-cells, which activates the microglial cells, which cuases excess/unbalanced kynurenines. For me the delay is around 24 hrs, which would be expected for IFN-g release, and seems also proportional to tryptophan transport into the brain.

You have an interesting theory. One way to test it might be to go to a gym and perform very heavy but non-aerobic exercise, such as a setting the weights on the gym machines very high, so that after just 8 lifting reps, your muscles are exhausted, and seeing if that causes PEM. You theory suggests it would.


Note however that in the Myhill, Booth and McLaren-Howard theory of PEM, it is the breakdown and loss of ATP molecules (they are in effect flushed out in the urine) which causes PEM. In this theory, the build up of lactic acid is an exacerbating factor, but is not the fundamental cause of PEM.

 

[Hutan]

Any simple way to test whether it's lactic acid build-up or IFN-g?

Well, you can get a lactic acid monitor to measure the lactic acid in peripheral blood.

I was pretty sure that the heavy aching fatigue in my limbs during and after mild brief exercise (eg hanging out the washing) was caused by lactic acid buildup. Sure enough to buy a monitor and test strips and analyse my blood.

I was very surprised to find that, in my case at least, it is not peripheral lactic acid that is causing that feeling.

(I've written up my experience on another thread here somewhere. I'm happy to lend the monitor to others in New Zealand. It would be good to hear of more experiences with this.)

 

[ryan31337]

I'm unconvinced about the involvement of lactic acid, at least for my case. I can do hours of walking normally without PEM, but a short walk that required a different stride, such as lifting my feet due to crusty snow, does cause it. I think the symptoms are triggered by muscle tearing, which activates the t-cells, which activates the microglial cells, which cuases excess/unbalanced kynurenines. For me the delay is around 24 hrs, which would be expected for IFN-g release, and seems also proportional to tryptophan transport into the brain.

My upper body is in worse condition than my legs, and it only takes a couple of minutes of unusual activity (sawing wood, washing windows, or doing pretty much anything with my arms above my head, to cause PEM (24 hrs later). It doesn't sound like that's the sort of activity and time frame for lactic acid problems. It does fit t-cell activation.

Exactly my experience of exercise too. When mild I was able to slowly build up to not insignificant amounts of exercise, 15-20 minutes swimming at pace for example, without too much PEM. But have me lift even a tiny dumbbell or work a muscle group in unusual daily activity that I hadn't very slowly built up previously and I'd be ruined the next day. Seems to be the polar opposite of many others that suggest short bursts of activity and weight lifting works for them.

I wonder how this variation fits with mitochondrial myopathy - I see exercise deemed helpful in those patients despite the chance it can worsen mutation & short-term symptoms. But who knows what researcher prejudice/misguidance is going on there too...

 

[Valentijn]

I wonder how this variation fits with mitochondrial myopathy - I see exercise deemed helpful in those patients despite the chance it can worsen mutation & short-term symptoms. But who knows what researcher prejudice/misguidance is going on there too...

All of the statements I've seen regarding the benefits of exercise in genetic mitochondrial disease come down to either 1) extrapolating from the benefits in healthy people, or 2) extremely short-term case studies. But there's also the very clear stipulation that exercise should stop if/when it's causing symptoms in those patients.

 

[arewenearlythereyet]

My experience is that running is as bad as lifting or carrying heavy weights for PEM. I can walk briskly for 20 minutes no problem If I run for 2 minutes I crash, if I lift 10kg I crash. If I walk continuously for 40 minutes I crash.

I think total ATP expenditure vs replenishment is part of the issue (certainly for me anyway). I also suspect that many of the metabolic pathways we use to create ATP happen simultaneously and at various degrees of efficiency throughout the body. I doubt its an on off switch where the body is doing just one form of energy production at any one time.

I think the changes from rest to exercise are significant, don't get me wrong, but we do use a large amount of ATP for all our base rate metabolism (75% or something like that) so it seems reasonable that we are probably using lipids amino s etc to do this at the same time.

I think what happens in my case is that I have an ATP replenishment rate that can't keep up with large slugs of ATP expenditure (running, lifting, sustained exercise etc). This still comes back to an inefficiency in energy production and I guess there is something that makes this replenishment efficiency vary from individual to individual?

 

[Wishful]

One thing I'm wondering is 'is there a subgroup of CFS with a time delay before PEM of around 24 hrs?' There seem to be people with widely varying delays, but maybe that's different mechanisms. If there's a cluster of patients with a consistent delay that matches IFN-g mediated symptoms, that should be a separate research target.

Should I set up a thread or poll asking about PEM delay? If so, are there any researchers who could suggest how best to pose the question?

 

[Dechi]

@Wishful Sure, open a new thread if you wish, it's a different subject.

For my part I thought PEM happened around 24-48 hours later for most people.

 

[Wishful]

I managed to get a few brain cells working and came up with a few more reasons why I don't think it's a lactic acid problem for me. One is that I get the same symptoms from socializing or other such mental activities as I do from physical exertion. Another is that I get the same effect from viral infections. A more critical point is that I don't see why there would be a 24 hr delay before muscle activity produced symptoms.

I can accept that there might be a problem in mitochondrial energy production, but I think it has to be occurring in my microglial cells, as a result of exterior chemical signalling.

 

[Basilico]

Thank you @Hip for that really clear and detailed explanation of energy metabolism - I will probably reread it multiple times.

I find the whole topic of PEM and lactic acid to be exceptionally confusing, because like with CFS/ME in general, there seems to be no hypothesis that holds true for everyone (or even most).

- Some people can tolerate movement/exercise as long as their heart rates don't cross a certain threshold.
- Some people can tolerate aerobic exercise as long as they don't do it for more than a certain amount of time or intensity.
- Some people can't tolerate any exercise at all

My husband, who has CFS, was a weightlifter for many years. Lifting weights is anaerobic, and if lactate acid were his problem, then he should have no issue with PEM. Yet, even if he drastically reduces the weights and the reps and the total number of exercises, he still gets PEM. He can't even do push-ups without risking PEM.

However, he can and has walked up to several hours with no problem.

I don't know how to make sense of this.

 

[Hip]

I find the whole topic of PEM and lactic acid to be exceptionally confusing, because like with CFS/ME in general, there seems to be no hypothesis that holds true for everyone (or even most).

It may simply be that there are subsets of ME/CFS patients, with each subset having blockages in different areas of their energy metabolism. In fact, this is exactly what Myhill, Booth and McLaren-Howard (MBM) found in their studies, and they subtype their ME/CFS patient cohort into Group B, Group A2 and Group A1 patients, depending on what blockages they have.

See this post for more info on these patient subset groups.

I understand that in the MBM theory, Group A patients are predicted to suffer from much more lactate production and acidosis as a result of exercise compared to Group B patients:

If what we see in neutrophil mitochondria also applies to muscle cells we would predict the following: Group A patients will have large PCr depletion, excess lactate production and high acidosis (depressed pH). Group B patients will have low PCr depletion (the shuttle is not needed for the ADK reaction), no excess lactate production and less acidosis for the same work load.

Source: Myhill 2012.

Note that Group B generally have more severe ME/CFS than Group A patients.



Of course, nowadays we have other theories of ME/CFS energy metabolism blockages to contend with: Fluge & Mella's paper which suggests the blockage may revolve around impaired pyruvate dehydrogenase function, and Dr Ron Davis's hypothesis that the blockage may revolve around impaired glycolysis (and in particular, an impaired pyruvate kinase enzyme in the glycolysis pathway).

 

[Basilico]

I'm unconvinced about the involvement of lactic acid, at least for my case. I can do hours of walking normally without PEM, but a short walk that required a different stride, such as lifting my feet due to crusty snow, does cause it. I think the symptoms are triggered by muscle tearing, which activates the t-cells, which activates the microglial cells, which causes excess/unbalanced kynurenines.

This got me thinking...perhaps for some (or many) PEM is caused by general inflammation instead of lactic acid.

We know there are microscopic tears in muscle fibers after exercise (which can happen even when doing mild exercise like walking).

In "normal" people, these tears are repaired and the muscle becomes stronger. What if in CFS people, these tears are triggering a cascade of inflammation responses that are actually responsible for PEM?

Maybe like @Hip mentioned, there are a subset who have lactic acid as the main cause, but for everyone else it has to do with an overzealous inflammation response that gets triggered by different levels of muscle "injury".

 

[Hip]

Maybe like @Hip mentioned, there are a subset who have lactic acid as the main cause, but for everyone else it has to do with an overzealous inflammation response that gets triggered by different levels of muscle "injury".

If I've understood it correctly, in the MBM theory, lactic acid is not the primary cause of PEM. Lactic acid is only a secondary factor, than may further exacerbate PEM.

In MBM, their theory of the cause of PEM centers on the temporary loss of ATP molecules in the cells. They say these ATP molecules are literally lost, and that this is the primary cause of PEM (ATP molecules are like delivery trucks that transport energy to where it is needed in the cell, so when these trucks are lost, there is no energy delivered).

The body takes several days to re-manufacture some new ATP molecules, and during this time, you remain in PEM until the new ATP molecules become available.

This MBM theory of PEM is explained in detail in two posts: this post (see the "Myhill, Booth and McLaren-Howard Theory of PEM" section), and more briefly in this post.

It does take a while to get to grips with the MBM theory of ME/CFS and PEM. I spent weeks if not months trying to understand it. It's best done slowly I found.

 

[Dechi]

@Hip what about the theory that lifting weights or doing exercise helps to reproduce new mitochondrias ? I know I've read about this somewhere. How does it fit in the MBM theory, or does it ?

There seems to be a trend for me, not sure yet, it's only been 2 years, but when I can't do my 4x15 seconds of lifting 2-3 times a week, it seems I get worse. It would make sense if this ATP reproduction my means of exercising is true !

 

[Basilico]

If I've understood it correctly, in the MBM theory, lactic acid is not the primary cause of PEM. Lactic acid is only a secondary factor, than may further exacerbate PEM.

In MBM, their theory of the cause of PEM centers on the temporary loss of ATP molecules in the cells. They say these ATP molecules are literally lost, and that this is the primary cause of PEM (ATP molecules are like delivery trucks that transport energy to where it is needed in the cell, so when these trucks are lost, there is no energy delivered).

The body takes several days to re-manufacture some new ATP molecules, and during this time, you remain in PEM until the new ATP molecules become available.

This MBM theory of PEM is explained in detail in two posts: this post (see the "Myhill, Booth and McLaren-Howard Theory of PEM" section), and more briefly in this post.

It does take a while to get to grips with the MBM theory of ME/CFS and PEM. I spent weeks if not months trying to understand it. It's best done slowly I found.

Thank you for those links - I've read the first in full (your posts are always very impressive!)

In thinking of how my husband gets PEM, I still can't wrap my head around something, maybe you have some insight.

If re-manufacturing ATP takes 1-4 days, then his PEM is inconsistent with a reaction to a deficiency of ATP.

Typically, if he overexerts himself passed his ever-changing threshold, he gets PEM instantaneously (there is rarely a delayed effect). Pretty immediately all of his normal symptoms will be super strong (very strong headache, dead arms/legs, nausea, zero energy, feeling like he was hit by a bus, inability to concentrate, etc...) but it can clear up in as little as a few hours and as far as I remember has never continued the next day.

So this doesn't fit with the idea that his reaction is caused by a lack of ATP since the timeframe doesn't fit, right?

(Incidentally, D-Ribose has never had any noticeable effect for him but liposomal glutathione does reduce or prevent his PEM - I don't understand how that could fit with either the lactic acid or the dysfunctional ATP hypothesis).

If Lactic Acid and deficient ATP are not the causes, I can't think of anything other than my "overzealous inflammation response" that makes sense in light of the (little) that I know. Do you have any thoughts on other PEM contributing factors?

 

[Mel9]

Thank you for those links - I've read the first in full (your posts are always very impressive!)

In thinking of how my husband gets PEM, I still can't wrap my head around something, maybe you have some insight.

If re-manufacturing ATP takes 1-4 days, then his PEM is inconsistent with a reaction to a deficiency of ATP.

Typically, if he overexerts himself passed his ever-changing threshold, he gets PEM instantaneously (there is rarely a delayed effect). Pretty immediately all of his normal symptoms will be super strong (very strong headache, dead arms/legs, nausea, zero energy, feeling like he was hit by a bus, inability to concentrate, etc...) but it can clear up in as little as a few hours and as far as I remember has never continued the next day.

So this doesn't fit with the idea that his reaction is caused by a lack of ATP since the timeframe doesn't fit, right?

(Incidentally, D-Ribose has never had any noticeable effect for him but liposomal glutathione does reduce or prevent his PEM - I don't understand how that could fit with either the lactic acid or the dysfunctional ATP hypothesis).

If Lactic Acid and deficient ATP are not the causes, I can't think of anything other than my "overzealous inflammation response" that makes sense in light of the (little) that I know. Do you have any thoughts on other PEM contributing factors?

Have you tested his blood sugar levels when he has these turns after exercise? (Is he 'hypo'?)

 

[Basilico]

Have you tested his blood sugar levels when he has these turns after exercise? (Is he 'hypo'?)

He actually has pre-diabetes (glucose intolerance and beginning stages of insulin resistance) but he does not have a true metabolic disorder; his pre-diabetes comes and goes and only tends to be a problem when he's in a flare up or is sleep deprived, and he is vigilant about keeping it in check.

He checks his blood glucose frequently and during PEM it is always (or usually) normal.

I wonder if hypoglycemia could cause PEM in some people. I don't think I've heard of anyone getting triggered like this, but maybe in conjunction with other dysregulations it could be a factor?

 

[Hip]

@Hip what about the theory that lifting weights or doing exercise helps to reproduce new mitochondrias ? I know I've read about this somewhere. How does it fit in the MBM theory, or does it ?

If the energy metabolism dysfunction in ME/CFS is caused by a factor in the blood serum which disables the mitochondria or disables glycolysis, which Fluge and Mella's investigations seem to suggest, then having new mitochondria will not help much, because those new mitochondria will very quickly be hit by the same factor.

Mitochondria are replaced pretty quickly anyway: there are several thousand mitochondria in each cell, and these have short lifespans, being replaced with new ones every 2 to 4 weeks (and some estimates suggest mitochondrial lifespans might be a short as 2 days before they are replaced).

Typically, if he overexerts himself passed his ever-changing threshold, he gets PEM instantaneously (there is rarely a delayed effect). Pretty immediately all of his normal symptoms will be super strong (very strong headache, dead arms/legs, nausea, zero energy, feeling like he was hit by a bus, inability to concentrate, etc...) but it can clear up in as little as a few hours and as far as I remember has never continued the next day.

So this doesn't fit with the idea that his reaction is caused by a lack of ATP since the timeframe doesn't fit, right?

There is a lot of variation in the way that ME/CFS patients experience PEM, at least judging by the reports of patients on this forum: for some it appears immediately after exercise, and for others it may not appear until the next day, or it may take several days before it appears. And in terms of duration, PEM usually lasts for at least 24 hours, but can last for several days or even several weeks. But the typical everyday PEM scenario would be a delayed onset, and the PEM period would last 1 to 4 days say.

The post exercise symptoms your husband experiences I guess could be PEM, but because their timescale is a bit unusual (ie, instant onset, and very rapid clear-up), it might be worth considering other causes. There is some info about exercise intolerance in this Wikipedia article:

Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at what would be considered to be the normally expected level or duration. It also includes experiences of unusually severe post-exercise pain, fatigue, nausea, vomiting or other negative effects. Exercise intolerance is not a disease or syndrome in and of itself, but can result from various disorders.